Abstract

AbstractSelf‐resistance genes are employed by many microbial producers of bioactive natural products to avoid self‐harm. Herein, we describe a unique strategy for self‐resistance toward a macrolide antibiotic, A26771B (1), identified by elucidating its biosynthetic pathway in the fungus Penicillium egyptiacum. A highly reducing polyketide synthase and a trans‐acting thioesterase generate the macrolide backbone, and a cytochrome P450 and an acyltransferase, respectively catalyze hydroxylation and succinylation to form the prodrug berkeleylactone E (2). Then, extracellular oxidative activation by a secreted flavin‐dependent oxidase forms 1, while intracellular reductive inactivation by a short‐chain reductase reforms 2, forming a redox cycle. Our work illustrates a unique redox‐mediated resistance mechanism for fungal antibiotics and contributes to the understanding of antibiotic biosynthesis and resistance.

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